tbuckley/cabot-search huggingface dataset:
Abstract 5822: YAP inhibition via targeting MAP3K3-dependent lysosomal degradation pathway overcomes BRAF and CDK4/6 inhibitor resistance
Authors: Won-Ji Ryu, Sanghyun Park, Tae Yeong Kim, Yumi Hwang, Hyun Ju Han, Jeong Dong Lee, Gun Min Kim, Joohyuk Sohn, Sang Kyum Kim, Joon Kim, Min Hwan Kim
Journal: Cancer Research (2023)

Abstract The Hippo-yes-associated protein (YAP) signaling pathway activation underlies the resistance to a wide range of molecularly targeted anti-cancer agents. However, strategies to block YAP activity in cancer by promoting YAP degradation have been largely unsuccessful despite rigorous investigations into canonical Hippo-YAP regulatory mechanisms. Here, we report a novel mechanism of YAP stability regulation by MAP3K3 independently of LATS-mediated proteasomal degradation. We observed that MAP3K3 depletion significantly reduced YAP protein levels in both normal and malignant cells, and mass spectrometry analysis revealed that MAP3K3 phosphorylates YAP at its serine 405 residue. MAP3K3-mediated serine 405 YAP phosphorylation polarizes YAP interaction with BTRC while hindering its interaction with FBXW7, collectively preventing both proteasomal degradation and the p62-mediated lysosomal degradation of YAP. We investigated the role of this mechanism in overcoming anti-cancer resistance and observed robust YAP activation in CDK4/6 inhibitor-resistant luminal breast cancer cells. Genetic and pharmacological MAP3K3 inhibition suppressed YAP-induced drug resistance. Moreover, increased MAP3K3 expression supported the pro-survival activity of YAP in BRAF inhibitor-resistant melanoma cells, and MAP3K3 depletion downregulated YAP-dependent cell cycle gene signatures. Accordingly, the combination of vemurafenib and ponatinib was effective in reducing the survival of BRAF inhibitor-resistant melanoma cells. Collectively, our study identified a novel phosphorylation-mediated YAP stability regulation mechanism and underscored MAP3K3 inhibition as a promising strategy to overcome BRAF and CDK4/6 inhibitor resistance by directly promoting YAP degradation. Citation Format: Won-Ji Ryu, Sanghyun Park, Tae Yeong Kim, Yumi Hwang, Hyun Ju Han, Jeong Dong Lee, Gun Min Kim, Joohyuk Sohn, Sang Kyum Kim, Joon Kim, Min Hwan Kim. YAP inhibition via targeting MAP3K3-dependent lysosomal degradation pathway overcomes BRAF and CDK4/6 inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5822.
Abstract 2215: Periostin plays a crucial role in the recurrence of head and neck squamous cell carcinoma
Authors: Jung Je Park, Ji Hyun Seo, Seongjun Won, Somi Ryu, Seung-Kuk Baek, Yoon Woo Koh
Journal: Cancer Research (2023)

Abstract Periostin (POSTN) is associated with many human tumors, such as colon, lung, breast, ovarian, prostate, and head and neck cancers. In this study, we focused on POSTN in Head and neck squamous cell carcinoma(HNSCC) because little is known about its possible role in carcinogenesis. This study aims to investigate the role of POSTN in the recurrence and prognosis of tongue cancer. A total of 97 patients diagnosed with tongue cancer in Gyeongsang National University Hospital between Jan 2012 and Dec 2017 were included. A retrospective review of medical records was performed, and the immunohistochemical staining with the POSTN antibody was done. Statistical analysis between cancer progression and POSTN expression was done. Referring to the clinical results that POSTN was related to the recurrence of tongue cancer, the effects of POSTN on HNSCC cell lines were investigated. Overexpression and depletion of POSTN were established in the HNSCC cell line. The results of POSTN in the HNSCC cell line were evaluated by colony-forming, migration, invasion, wound healing, and flow cytometry in vitro and in vivo. We also investigated the effects of POSTN overexpression and depletion on invasion, migration, and cell apoptosis. High expression of POSTN in HNSCC was related to cancer recurrence. In multivariate analyses, High expression of POSTN was a statistically significant risk factor for tongue cancer recurrence (HR, 16.8; p=0.040). Also, POSTN inhibits colony-forming, migration, invasion, and wound healing. This study showed that POSTN in HNSCC is a positive correlation with recurrence. And we also confirmed that POSTN promoted tumor progression in vitro and in vivo. POSTN plays an essential role in the growth and metastasis of tongue cancer and may be positioned as a therapeutic target for head and neck cancer. Citation Format: Jung Je Park, Ji Hyun Seo, Seongjun Won, Somi Ryu, Seung-Kuk Baek, Yoon Woo Koh. Periostin plays a crucial role in the recurrence of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2215.
Abstract 1475: FOXO transcription factors regulate WNT pathway gene expression in GBM
Authors: Megan Keniry, Shania Pintor, Alma Lopez, David Flores
Journal: Cancer Research (2023)

Abstract Basal-like breast cancer (BBC) and Glioblastoma Multiforme (GBM) are aggressive cancers associated with poor prognosis. BBC and GBM express stem gene expression signatures which are in part driven by FOXO transcription factors. To gain further insight into the impact of FOXO1 in BBC, we treated BT549 cells with the FOXO1 inhibitor AS1842856 and performed RNA Seq. Gene Set Enrichment Analysis (GSEA) with RNA Seq. data indicated that a set of WNT target genes including LEF1 and AXIN2 were robustly induced after 48-hours of AS1842856 treatment. These same genes were also induced in GBM cell lines U87MG, LN18, LN229, A172, and DBTRG upon AS1842856 treatment. RNAi targeting of FOXO1 led to reduced LEF1 gene expression in BT549 and U87MG cells at 18-hour and 24-hour timepoints respectively. CRISPR Cas9-mediated FOXO1 disruption led to reduced expression of canonical WNT target gene LEF1 in U87MG cells. Citation Format: Megan Keniry, Shania Pintor, Alma Lopez, David Flores. FOXO transcription factors regulate WNT pathway gene expression in GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1475.
Abstract 1106: A novel cancer therapy using proton beam; an integrated proton dynamic therapy, iPDT
Authors: HIrofumi Matsui
Journal: Cancer Research (2023)

Abstract A super-aged society, the prime example of which is Japan, is being flooded with increasing in numerous numbers of aged cancer patients, who often take anti-coagulant medicines to prevent the attacks of ischemic heart diseases and/or strokes. Since they show bleeding tendency induced by the medicines, it’s hard for them to receive surgical operations. Thus, low invasive cancer treatments without bleedings are abundantly desired. In this study, the applicant will establish a new proton therapy, in which a resonance nuclear reaction (RNR) induced by collision of a proton with a stable nitrogen isotope (15N), can be a clue to injure cancer-cells specifically. The LET of the product ions (12C6+, 4He2+) of the 15N RNR is above 50 times in comparison with the LET of proton. To establish the cancer-specific 15N delivery, 15N-aminolevulinic acid (15N-ALA) will be used. This reagent has been already used and obtained regulatory approvals as a diagnostic medicine for the location of the glioblastoma in Japan. In this study, a pair of rat gastric epithelial cells, one is normal cell, and another is cancerous characteristics cells were used. 15N-ALA treated porphyrin fluorescent intensity of these cells will be compared with 14N-ALA treatment. The cells will be irradiated with a proton beam generated by an electrostatic accelerator and 4.43 MeV gamma-rays will be measured to demonstrate the amount of 15N collected specifically in the tumor cells. Such quantitative analysis of 15N in the tumor cells can be a new pre-diagnosis of iPDT. Citation Format: HIrofumi Matsui. A novel cancer therapy using proton beam; an integrated proton dynamic therapy, iPDT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1106.
Abstract 4168: BALB/c-CD3EDG HuGEMMTM mouse model for evaluation of CD3-targeted tumor immunotherapy
Authors: Demi Xiaojuan Liu, Kaixia Lian, Xuefei Yan, Jie Lin, Lei Zheng, Annie Xiaoyu An, Xiaoxi Xu, Ludovic Bourre, Jingjing Wang
Journal: Cancer Research (2023)

Abstract Introduction: T cell immune response plays critical roles in cancer immunotherapy. CD3 complex, composed of CD3ε, CD3δ and CD3γ chains, is an essential component of TCR-CD3 complex mediating TCR signaling. Targeting CD3 complex has therefore become a popular strategy for manipulation of T cell function. Clinically relevant animal models for proper evaluation of human CD3 antibodies is in great demand in the field. Currently, adoptive transfer of human CD3+ T cells or transplantation of human hematopoietic stem/precursor cells to immunodeficient mice are usually employed. However, these mouse models are not fully immunocompetent. In this study we have evaluated in vitro CD3 EDG functionality and in vivo therapeutic efficacy, in BALB/c-hCD3EDG knock-in mouse in which all the three components of the CD3 complex — Cd3ε, Cd3δ, and Cd3γ— are replaced by their human counterparts, CD3E, CD3D, and CD3G. Methods: A humanized CD3EDG mouse model (HuGEMM) on BALB/c background was generated by replacing the entire mouse CD3EDG with its human counterpart through ES cell-based gene targeting. The cell surface expression of CD3E and intracellular expression of CD3D and CD3G were confirmed by FACS. Naïve CD3+ T cells were isolated from the splenocytes of homozygous CD3EDG HuGEMM and activated by anti-hCD3 antibody. T cell proliferation was demonstrated by CFSE dilution assay. To validate the TCR functionality of humanized CD3EDG in vivo, we evaluated bispecific antibody anti-hCD3/hEpCAM5 in BALB/c-CD3EDG HuGEMM bearing CT26-hEpCAM5. Results: The expression of human CD3E, CD3D and CD3G were confirmed by flow cytometry. hEpCAM5 antigen expression was confirmed in CT26 cell line in vitro and tumor in vivo by flow cytometry. The TCR functionality was detected by in vitro T cell activation assays using anti-hCD3 antibody. In vivo efficacy was demonstrated using a bispecific antibody that simultaneously binds to human CD3 and human tumor associated antigen EpCAM5 in human CD3 EDG knock-in mice engrafted with CT26-hEpCAM5 tumor. The therapeutic efficacy of the bispecific antibody showed 32% tumor growth inhibition compared to control treatment. No significant body weight loss was recorded in any of the animals. Conclusion: This study showed the successful establishment of humanized CD3 knock-in BALB/c mouse models providing a full immunocompetent model for human CD3-targeted tumor immunotherapies evaluation. Citation Format: Demi Xiaojuan Liu, Kaixia Lian, Xuefei Yan, Jie Lin, Lei Zheng, Annie Xiaoyu An, Xiaoxi Xu, Ludovic Bourre, Jingjing Wang. BALB/c-CD3EDG HuGEMMTM mouse model for evaluation of CD3-targeted tumor immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4168.
Abstract 5833: Crosstalk between cancer-associated fibroblasts and CD8 T cells leads to improved T cell activation in head and neck cancer
Authors: Diana Graves, Aleksandar Obradovic, Henry Schares, Michael Korrer, Brian Bachmann, Young Kim, Ben Park, Paula Hurley
Journal: Cancer Research (2023)

Abstract Cancer-associated fibroblasts (CAFs) have been shown to modulate immune responses in the tumor microenvironment (TME), however, the extensive heterogeneity of these cells has precluded rigorous understanding of their immunoregulatory role in the head and neck TME. To gain a better understanding of the relationship between CAFs and the immune environment in head and neck cancer, we leveraged protein activity inference tools to analyze single-cell RNA sequencing of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients pre- and post-treatment with the αPD-1 therapy, nivolumab. From this analysis, we identified a novel CAF population predictive of patient response to αPD-1 therapy. Utilizing in vitro co-culture assays with primary human CD8 T cells, we discovered that this novel CAF population was able to elicit features associated with enhanced CD8 T cell function, namely the reduction of PD-1+TIM-3+ exhaustive phenotypes and induction of CD103+NKG2A+ tissue-resident memory phenotypes and cytotoxicity. Due to their unique ability to stimulate T cells in this manner, we termed this novel CAF population T cell-stimulating CAFs (tsCAFs). In efforts to elucidate the mechanism behind this pro-inflammatory function, we determined that tsCAFs secrete a heat-sensitive small molecule/s in order to alter CD8 T cell behavior. However, tsCAFs will only secrete this factor in the presence of activated T cells demonstrating crosstalk between T cells and CAFs in the head and neck TME. This pro-inflammatory crosstalk between CAFs and T cells represents a novel finding that further contributes to the idea of immunoregulatory pleiotropy among CAFs. Accordingly, our findings highlight the functional importance of distinct CAF subsets in modulating the immunoregulatory milieu of human HNSCC and warrant more extensive characterization of CAF-T cell interactions in human squamous cell carcinoma. Citation Format: Diana Graves, Aleksandar Obradovic, Henry Schares, Michael Korrer, Brian Bachmann, Young Kim, Ben Park, Paula Hurley. Crosstalk between cancer-associated fibroblasts and CD8 T cells leads to improved T cell activation in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5833.
Abstract 4742: Familial adenomatous polyposis epigenetic landscape as a precancer model of colorectal cancer
Authors: Hayan Lee, Gat Krieger, Tyson Clark, Yizhou Zhu, Aziz Khan, Casey R. Hanson, Aaron Horning, Edward D. Esplin, Mohan Badu, Kristina Paul, Roxanne Chiu, Bahareh Bahmani, Stephanie Nevins, Annika K. Weimer, Ariel Jaimovich, Christina Curtis, William Greenleaf, James M. Ford, Doron Lipson, Zohar Shipony, Michael P. Snyder
Journal: Cancer Research (2023)

Abstract Aberrant shifts in DNA methylation have long been regarded as an early biomarker for cancer onset and progression. However, it is unclear when methylation aberrance starts and how it interacts with other epigenomic modifications. To address how epigenomic changes occur and interact during the transformation from normal healthy colon tissue to malignant colorectal cancer (CRC), we collected 51 samples from 15 familial adenomatous polyposis (FAP) and non-FAP colorectal cancer patients. We generated 30-70x of whole-genome enzymatic methylation sequencing (WGEM-seq) data via the novel Ultima Genomics ultra high-throughput sequencing platform. We observed hypermethylation and hypomethylation emerge early in the malignant transformation process in gene promoters and distal regulatory elements. We performed multifaceted analysis on methylation alterations with whole-genome sequencing (WGS), transposase accessibility (ATAC-seq), high-resolution chromatin accessibility (Tri-C), and gene expression (RNA-seq) data. Our multidimensional analysis demonstrates how collectively epigenomic alterations have affected gene expression throughout normal colon mucosa, benign and dysplasia polyps to adenocarcinoma. Epigenomic changes start as early as benign polyps, followed by other epigenomic shifts, including bivalent domains. Various epigenomic aberrances are associated with concomitant gene expression level changes. Our integrative analysis of multi-epigenomics data implicates collective and cumulative epigenomic instability in the early onset of colon carcinogenesis. Citation Format: Hayan Lee, Gat Krieger, Tyson Clark, Yizhou Zhu, Aziz Khan, Casey R. Hanson, Aaron Horning, Edward D. Esplin, Mohan Badu, Kristina Paul, Roxanne Chiu, Bahareh Bahmani, Stephanie Nevins, Annika K. Weimer, Ariel Jaimovich, Christina Curtis, William Greenleaf, James M. Ford, Doron Lipson, Zohar Shipony, Michael P. Snyder. Familial adenomatous polyposis epigenetic landscape as a precancer model of colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4742.
Abstract 1867: Pre-clinical characterization of anti-CEACAM1 antibody
Authors: Jinyu Dong, Yu Zhang, Baiyang Wang, Tingting Pu, Liegang Shao, Binbin Wang, Dong Wang, Jie Ni, Sunan Li, Xin Dong
Journal: Cancer Research (2023)

Abstract Targeting checkpoint molecules cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed death receptor-1 (PD-1) expressed on immune cells has shown promising results in the treatment of cancer patients. Nevertheless only a small portion of population benefited from current ICI treatments, so there should be other mechanisms for immune evasion potentially. The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an activation-induced inhibitory molecule on T and NK cells. In a wide range of cancers, it’s also expressed on tumor cells and other immune cells including macrophages and neutrophils. Homophilic interaction between CEACAM1 expressed on tumor cells and immune cells dampens NK and T cell function, mediates tumor migration, and promotes tumor angiogenesis, which implies that this homophilic interaction is an important mechanism for tumor progression. Here, we describe the identification and characterization of a novel humanized anti-human CEACAM1 therapeutic antibody developed via Neologics’ novel target validation and antibody screening Tier-A platform. This anti-CEACAM1 antibody specifically binds to recombinant human CEACAM1 with nM level affinity and significantly enhances T cell activities and NK killing on CEACAM1 expressing tumor cells, inhibits tumor cell migration in vitro as well. In humanized mouse models, this antibody evidently reduces tumor growth alone or combined with other immune checkpoint blockers. Taken together, we have demonstrated this anti-CEACAM1 antibody specifically enhance NK cell activity, modulate T cell immune activation and inhibit tumor migration supporting further clinical investigation for various indications. Citation Format: Jinyu Dong, Yu Zhang, Baiyang Wang, Tingting Pu, Liegang Shao, Binbin Wang, Dong Wang, Jie Ni, Sunan Li, Xin Dong. Pre-clinical characterization of anti-CEACAM1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1867.
Abstract 2910: NKG2A suppression enhances the function of primary human Natural Killer cells
Authors: Tayler J. Croom-Perez, Liza D. Robles-Carrillo, Md Faqrul Hasan, Alicja J. Copik
Journal: Cancer Research (2023)

Abstract In this study we propose inhibition of NKG2A signaling enhances the anti-tumor response of primary human NK cells. One mechanism employed by tumor cells to evade immunosurveillance is through induction of the surface expression of unconventional HLA ligands that agonize inhibitory receptors on immune cells. Specifically on some tumors, HLA-E is either expressed or its expression is known to be induced by IFNγ and is indicative of resistance to immunotherapy. HLA-E agonizes the CD94/NKG2A inhibitory complex on NK cells and some T cells to lessen their cytotoxicity, potentially decreasing the efficacy of cellular therapy with these immune cells. In this study ex vivo-expanded primary human NK cells were shown to have significantly elevated expression of NKG2A. These expanded NK cells also secreted high levels of IFNγ and could induce expression of HLA-E on tumor cells. Suppression of NKG2A by either antibody blockade or gene deletion increased the cytotoxicity of NK cells against the lung cancer cell line A549 stably expressing HLA-E. NKG2A knockout cells had an almost 10-fold decrease in EC50 compared to wild-type NK cells (EC50 0.15 vs 0.94 at 48 h), meaning nearly log-fold fewer NKG2A knockout cells are needed to kill the same number of tumor cells. The effect of NKG2A knockout on cytotoxicity of NK cells against other cancer cell lines stably expressing HLA-E will be presented along with effects of NKG2A suppression on NK cell phenotype, cytokine secretion and degranulation. These initial data suggest that blockade of the CD94/NKG2A inhibitory complex can improve the function of ex vivo expanded human NK cells and could provide an effector population with the potential for enhanced therapeutic efficacy. Citation Format: Tayler J. Croom-Perez, Liza D. Robles-Carrillo, Md Faqrul Hasan, Alicja J. Copik. NKG2A suppression enhances the function of primary human Natural Killer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2910.